Delta-9-tetrahydrocannabinol (.DELTA..sup.9 -THC) is the active ingredient of the plant Cannabis sativa (marijuana) which is responsible for the majority of the pharmacological effects of the plant. Many of the pharmacologic properties of the marijuana plant or .DELTA..sup.9 -THC could be directed to specific therapeutic effects given the appropriate dosage form. Therapeutic activities associated with marijuana use or administration of .DELTA..sup.9 -THC include, but are not limited to, antiemetic activity as disclosed in Sallan, S. E.; Zinberg, N. E.; and Frei, E., III. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N. Engl. J. Med., 293:795-797, 1975; Sallan, S. E.; Cronin, C.; Zelen, M.; and Zinberg, N. E. Antiemetics in patients receiving chemotherapy for cancer. N. Engl. J. Med., 302:135-138, 1980; Ungerleider, J. T.; Fairbanks, L. A.; and Andrysiak, T. THC or compazine for cancer chemotherapy patient--the USLA Study, Part II: Patient drug preference. Am. J. Clin. Oncol., 8:142-147, 1985; and Regelson, W.; Butler, J. R.; Schultz, J.; Kirk, T.; Peek, L.: Green, M. L.; and Zalis, M. O. The Pharmacology of Marihuana , Vol. 2, Eds. M. C. Braude and S. Szara, Raven Press, N.Y., 1976, pp. 763-776,
Analgesic activity is disclosed in Maurer, M.; Henn, V.; Dittrich, A.; and Hofmann, A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur. Arch. Psychiatry Clin. Neurosci., 240(1):1-4, 1990; Noyes, R.; Brunk, S. F; Avery, D. H.; and Canter, A. Psychologic effects of oral delta-9-tetrahydrocannabinol in advanced cancer patients. Compr. Psychiat., 17(5):641-646, 1976; and Regelson et al. ibid.
Anti-spasticity is discussed in Maurer et al. ibid.
Appetite stimulation is noted by Maurer et al. and Noyes et al. ibid and Gagnon, M. A. and Eli, R. Les effets de la marijuana et de la d-amphetamine sur l'appetit, la consommation alimentire et quelques variables cardio-respiratoires chez l'homme (Effects of marihuana and of d-amphetamine on appetite, food intake, and some cardio-respiratory variables in man). Union Med. Can., 104(6):914-921, 1975; Foltin, R. W.; and Fischmann, M. W. Behavioral analysis of marijuana effects on food intake in humans. Pharmacol. Biochem. Behav., 30(2):551, 1988; Foltin, R. W.; Brady, J. V.; and Fischman, M. W. Behavioral analysis of marijuana effects on food intake in humans. Pharmacol. Biochem. Behav., 25(3), 557-582, 1986; Bruera, E. Current pharmacological management of anorexia in cancer patients. Oncologly, Williston Park, 6(1), 125-130, 1992).
Antidepressant activity is discussed in Regelson et al and Maurer et al, ibid.
Treatment and prevention of migraine headache is discussed by El-Mallakh, R. S. Marihuana and migraine. Headache, 27(8):442-443, 1987; and Volfe, Z.; Dvilansky, A.; and Nathan, I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int. J. Clin. Pharmacol. Res., 5(4):243-246, 1985.
Anti-anxiety is disclosed by McLendon, D. M.; Harris, R. T.; and Maule, W. F. Suppression of the cardiac conditioned response by delta-9-tetrahydrocannabinol: A comparison with other drugs. Psychopharmacology, 50(2):159-163, 1976; and Musty, R. E. Possible anxiolytic effects of cannabidiol. The Cannabinoids: Chemical, Pharmacologic, and Therapeutic aspects, Eds. S. Agurell, W. L. Dewey, and R. E. Willette, Academic Press, Orlando, Fla., 1984).
Treatment of glaucoma is the subject of Hepler, R. S.; Frank, I. M.; and Petrus R. Occular effects of marihuana smoking. In: The Pharmacology of Marihuana, Eds. M. C. Braude and S. Szara, Raven Press, N.Y., 1976, pp. 815-824; El Solhy, M. A.; Harland, E.; and Waller, C. W. Cannabinoids in Glaucoma II: The effect of different cannabinoids on the intraocular pressure of the rabbit. Curr. Eye Res., 3(6):841-850, 1984).
Improvement of night vision is taught by Reese, K. M. Cannahis seems to improve night vision of fisherman. Chem. Eng. News. 69(31):44, 1991; and West, M. E. Cannabis and night vision. Nature. 351(6329):703-704, 1991).
Formulation of .DELTA..sup.9 -THC to be used as a medicinal agent has been problematic. Orally, .DELTA..sup.9 -THC was found to be poorly absorbed
(Ohlsson, A.: Lindgren, J. E.; Wahlen, A.; Agurell, S.; Hollister, L. E.; Gillespie, B. A. Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin. Pharmacol. Ther. 28:409-416, 1980) with erratic bioavailability which is dependent on food intake
(Pryor, G. T.; Husain, S.; Mitoma, C. Influence of fasting on the absorption and effects of delta-9-THC after oral administration of sesame oil. Pharmacol. Biochem Behav., 6:331,341, 1976). From suppository formulations (both lipophilic and hydrophilic) there was no absorption of .DELTA..sup.9 -THC
(Perlin, E.; Smith C. G.; Nichols, A. I.; Almirez, R.; Flora, K. P.; Craddock, J. C.; and Peck, C. C. Disposition and bioavailability of various formulations of tetrahydrocannabinol in the Rhesus monkey. J. Pharm. Sci., 74:171-174, 1985). The only formulation resulting in good bioavailability was an intramuscular injectable (Perlin et al. ibid) where .DELTA..sup.9 -THC was formulated in Tween 80 (39 .+-. 13% bioavailability) or Emulphor-El 620 (102 .+-. 15% bioavailability). Injectibles are fraught with the problems of being invasive and requiring professional assistance (phlebotomist), and therefore in many cases preclude self medication.
In 1991 El Sohly et al. (El Sohly, M. A.; Stanford, D. F.; Harland, E. C.; Hikal, A. H.; Walker, L. A.; Little, T. L., Jr.; Rider, J. N.; and Jones, A. B. Rectal bioavailability of .DELTA..sup.9 -tetrahydrocannabinol from the hemisuccinate ester in monkeys. J. Pharm. Sci., 80(10):942-945, 1991.
El Sohly, M. A.; Little, T. L., Jr.; Hikal, A. H.; Harland, E.; Stanford, D. F.; and Walker, L. Rectal bioavailability of delta-9-tetrahydrocannabinol from various esters. Pharmacol. Biochem. Behav., 40:497-502, 1991) reported on the development of a suppository formulation containing the hemisuccinate ester of .DELTA..sup.9 -THC as a prodrug. This formulation resulted in high consistent bioavailability of .DELTA..sup.9 -THC. Although the prodrug .DELTA..sup.9 -THC-hemisuccinate was reasonably stable in the lipophilic base used for the suppository formulation, the stability was not enough to provide the shelf life required for the product to be marketed. It was therefore necessary to develop a formulation which would provide the required stability and shelf life.
It is an object of the present invention to provide a suppository formulation containing at least one bioavailable .DELTA..sup.9 -THC derivative in which the suppository has long term stability and shelf life.